Identifying and understanding the risk factors associated with diabetes is invaluable for the development and evaluation of effective intervention strategies.
Lacking normal regulatory mechanisms, diabetics are encouraged to strive for optimal control through a modulated life style approach that focuses on dietary control, exercise, and glucose self-testing with the timely administration of insulin or oral hypoglycemic medications. Invasive forms of self-testing are painful and fraught with a multitude of psychosocial hurdles, and are resisted by most diabetics. Alternatives to the currently available invasive blood glucose testing are highly desirable.
Conventional approaches to non-invasive alternatives seek to reduce or eliminate the skin trauma, pain, and blood waste associated with traditional invasive glucose monitoring technologies. In general, though never effectively demonstrated prior to this invention, noninvasive optical blood glucose monitoring requires no bodily fluid samples be withdrawn from tissue and involves external irradiation with electromagnetic radiation and measurement of the resulting optical flux (e.g., fluorescence or diffuse reflectance). In theory, but not in practice, glucose levels would be derived from the spectral information following comparison to reference spectra for glucose and background interferants, reference calibrants, and/or application of advanced signal processing mathematical algorithms.
Radiation-based technologies, which are often referred to as potential candidates for solving the non-invasive glucose problem, have included variations of sampling and data processing methods including: 1) mid-infrared (MIR) spectroscopy, 2) near-infrared radiation (NIR) spectroscopy, 3) radio wave impedance, 4) autofluorescence and white light scattering, and 5) Raman spectroscopy. Each of these methods uses optical sensors and relies on the premise that the absorption or fluorescence pattern of electromagnetic radiation can be quantitatively related to a change in blood glucose concentration. However, other endogenous substances including, but not limited to, water, lipids, proteins, and hemoglobin are known to absorb energy, particularly infrared light and can easily obscure the relatively weak glucose signal.
Other approaches to non-invasive glucose measurements are based on microvascular changes in the retina, acoustical impedance, nuclear magnetic resonance (NMR) spectroscopy and optical hydrogels that quantify glucose levels in tear fluid. While putatively non-invasive, these technologies have yet to be demonstrated as effective in clinical testing.
Nearly noninvasive techniques tend to rely on interstitial fluid extraction from skin. This can be accomplished using permeability enhancers, sweat inducers, and/or suction devices with or without the application of electrical current. One device recently approved by the FDA relies on reverse iontophoresis, utilizing an electrical current applied to the skin. The current pulls out salt, which carries water, which, in turn, carries glucose. The glucose concentration of this recovered fluid is measured and is proportional to that of blood. In keeping with its nearly noninvasive description, this technology is commonly associated with some discomfort and requires at least twice daily calibrations against conventional blood glucose measurements (e.g. invasive lancing).
Other nearly noninvasive blood glucose monitoring techniques similarly involve transcutaneous harvesting for interstitial fluid measurement. Other technologies for disrupting the skin barrier to obtain interstitial fluid include: 1) dissolution with chemicals; 2) microporation with a laser; 3) penetration with a thin needle; and/or 4) suction with a pump. Minimally invasive blood glucose monitoring can also involve the insertion of an indwelling glucose monitor under the skin to measure the interstitial fluid glucose concentration. These monitors typically rely on optical or enzymatic sensors. Although technologically innovative, these in situ sensors have had limited success. Implantable glucose oxidase (“GO”) sensors have been limited by local factors causing unstable signal output, whereas optical sensors must overcome signal obfuscation by blood constituents as well as interference by substances with absorption spectra similar to glucose. Moreover, inflammation associated with subcutaneous monitoring may contribute to systematic errors requiring repositioning, recalibration or replacement, and more research is needed to evaluate the effects of variable local inflammation at the sensor implantation site on glucose concentration and transit time.
Interstitial fluid glucose concentrations have previously been shown to be similar to simultaneously measured fixed or fluctuating blood glucose concentrations. See, e.g., Bantle et al., Journal of Laboratory and Clinical Medicine 130:436-441, 1997; Sternberg et al., Diabetes Care 18:1266-1269, 1995. Such studies helped validate noninvasive/minimally invasive technologies for blood glucose monitoring, insofar as many of these technologies measure glucose in blood as well as interstitial fluid.
A noninvasive glucose monitor that is portable, simple and rapid to use, which provides accurate clinical information is desirable. In particular, the ability to derive first and second order information in real-time for dynamic glucose metabolism, such as the direction and rate of change of bioavailable glucose distributed within the blood and interstitial fluid space, would be extremely important for continuous and discrete glucose monitoring.